NQO2 is a reactive oxygen species generating off-target for acetaminophen

[Image: see text] The analgesic and antipyretic compound acetaminophen (paracetamol) is one of the most used drugs worldwide. Acetaminophen overdose is also the most common cause for acute liver toxicity. Here we show that acetaminophen and many structurally related compounds bind quinone reductase 2 (NQO2) in vitro and in live cells, establishing NQO2 as a novel off-target. NQO2 modulates the levels of acetaminophen derived reactive oxygen species, more specifically superoxide anions, in cultured cells. In humans, NQO2 is highly expressed in liver and kidney, the main sites of acetaminophen toxicity. We suggest that NQO2 mediated superoxide production may function as a novel mechanism augmenting acetaminophen toxicity

Minimal hepatic toxicity of Onyx-015: spatial restriction of coxsackie-adenoviral receptor in normal liver.

We administered an adenoviral vector, Onyx-015, into the hepatic artery of patients with metastatic colorectal cancer involving the liver. Thirty-five patients enrolled in this multi-institutional phase I/II trial received up to eight arterial infusions of up to 2 x 10(12) viral particles. Hepatic toxicity was the primary dose-limiting toxicity observed in preclinical models. However, nearly 200 infusions of this adenoviral vector were administered directly into the hepatic artery without significant toxicity. Therefore, we undertook this analysis to determine the impact of repeated adenoviral exposure on hepatic function. Seventeen patients were treated at our institution, providing a detailed data set on the changes in hepatic function following repeated exposure to adenovirus. No changes in hepatic function occurred with the first treatment of Onyx-015 among these patients. Transient increases in transaminase levels occurred in one patient starting with the second infusion and transient increases in bilirubin was observed in two patients starting with the fifth treatment. These changes occurred too early to be explained by viral-mediated lysis of hepatocytes. In addition, viremia was observed starting 3-5 days after the viral infusion in half of the patient, but was not associated with hepatic toxicity. To further understand the basis for the minimal hepatic toxicity of adenoviral vectors, we evaluated the replication of adenovirus in primary hepatocytes and tumor cells in culture and the expression of the coxsackie-adenoviral receptor (CAR) in normal liver and colon cancer metastatic to the liver. We found that adenovirus replicates poorly in primary hepatocytes but replicates efficiently in tumors including tumors derived from hepatocytes. In addition, we found that CAR is localized at junctions between hepatocytes and is inaccessible to hepatic blood flow. CAR is not expressed on tumor vasculature but is expressed on tumor cells. Spatial restriction of CAR to the intercellular space in normal liver and diminished replication of adenovirus in hepatocytes may explain the minimal toxicity observed following repeated hepatic artery infusions with Onyx-015

Systems biology for identifying liver toxicity pathways

Drug-induced liver toxicity is one of the leading causes of acute liver failure in the United States, exceeding all other causes combined. The objective of this paper is to describe systems biology methods for identifying pathways involved in liver toxicity induced by free fatty acids (FFA) and tumor necrosis factor (TNF)-α in human hepatoblastoma cells (HepG2/C3A). Systems biology approaches were developed to integrate multi-level data, i.e., gene expression, metabolite profile, toxicity measurements and a priori knowledge to identify gene targets for modulating liver toxicity. Targets that modulate liver toxicity, in vitro, were computationally predicted and some targets were experimentally validated

The effects of two pesticides on Clarias gariepinus

Bioassays were carried out to determine the toxicity of two pesticides, Roundup and Gramoxone on Clarias gariepinus. The acute toxicity of both pesticides decreased towards the end of the bioassay period. The calculated safe concentrations for Roundup and Gramoxone are 0.99 ppm - 0.99 ppm and 0.09 ppm - 0.9 ppm respectively. Histological examination revealed that there were pathological changes in the gills and liver even when the fish were subjected to sub-lethal level

ASSESSMENT OF EXTRAPULMONARY TOXICITY INDUCED BY CARBON NANOMATERIALS FOLLOWING INTRA-TRACHEAL INSTILLATION IN RATS

Objective: Carbon nanomaterials (CNMs) such as carbon nanofibres (CNFs), multi wall carbon nanotubes (MWCNTs) and carbon nanorods (CNRs) were found various industrial and commercial applications. The occupational exposure for these CNMs were also increased enormously. The present study evaluated the extrapulmonary toxicity induced by these CNMs. Methods: The extrapulmonary toxicity was assessed following intratracheal instillation of test CNMs in rats after 1 day, 1 week, 1 month and 3 months post exposure periods by using serum biochemical parameters such as alanine transaminase (ALT) and creatinine using diagnostic assay kits. Further, the histopathological analysis was performed for liver and kidneys of particle exposed rats.Results: The results have displayed that increased levels of serum ALT and creatinine were found after 1 day, 1 week and 1 month post exposure periods indicating liver and kidney toxicity respectively. This toxicity was further confirmed by the changes observed in the histopathological analysis of rat liver and kidneys.Conclusion: The CNFs, MWCNTs and CNRs able to translocate from the lungs into other extrapulmonary organs such as liver and kidney, and also cause dose dependent toxicity to them